Aptamer Design for VEGF Binding and Toxicity Reduction
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Solution Overview
Problem
Current anti-VEGF drugs have limited efficacy and duration, and existing aptamers like Macugen fail to recognize all VEGFA isoforms, necessitating the development of more specific and effective aptamers targeting VEGF and/or Ang2 for treating neovascular retinal diseases.
Innovation Solution
Development of anti-VEGF and anti-Ang2 aptamers with enhanced binding affinity and specificity, capable of binding to multiple VEGFA isoforms and Ang2, respectively, and forming specific secondary structures, which are nuclease-resistant and effective across various species, to inhibit interactions with their receptors and treat neovascular diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the dosage of anti-VEGF agents is increased to improve potency and duration, then therapeutic efficacy is improved, but drug toxicity and side effects increase
Solution Approach 1:
The patent changes the molecular parameters of the therapeutic agent by using aptamers with approximately 15 kDa molecular weight and high solubility, enabling achievement of high molar dosage without proportionally increasing mass dosage, thus improving efficacy while avoiding toxicity associated with higher mass dosages of conventional drugs
Solution Approach 2:
The patent uses aptamers as synthetic copies that mimic the binding function of larger proteins but with optimized properties including smaller size, higher solubility, and nuclease resistance, allowing for improved pharmacokinetic profile and reduced toxicity
2Reliability
If an aptamer is designed to bind to all VEGFA isoforms with high affinity, then binding specificity is improved, but aptamer sequence complexity increases
Solution Approach 1:
The patent designs aptamers with universal binding capability across all VEGFA isoforms (VEGF-121, VEGF-165, VEGF-189) and multiple species (human, mouse, rat, rabbit, monkey), allowing a single aptamer sequence to perform multiple binding functions without requiring isoform-specific variants
Solution Approach 2:
The patent achieves broad specificity through optimized nucleotide sequences and secondary structures that recognize conserved epitopes across VEGFA isoforms, maintaining binding affinity KD ≤ 20 nM while keeping aptamer lengths manageable (typically 20-100 nucleotides)
3Quantity of substance
If an aptamer is formulated at high concentration to achieve high molar dosage, then solubility is improved, but aggregation and precipitation increase
Solution Approach 1:
The patent formulates aptamers at concentrations of 200 mg/ml or higher by optimizing aptamer sequence composition, secondary structure stability, and formulation conditions, achieving high molar dosage while maintaining solution stability and preventing aggregation through careful control of pH, ionic strength, and excipients
4Quantity of substance
If a small molecular weight aptamer is used to achieve high solubility and high molar dosage, then bioavailability is improved, but resistance to nuclease degradation decreases
Solution Approach 1:
The patent creates composite nucleic acid structures by incorporating modified nucleotides (such as 2'-O-methyl, LNA, or phosphorothioate modifications) into the aptamer sequence, combining the advantages of small size and high solubility with enhanced resistance to nuclease degradation
Solution Approach 2:
The patent modifies the chemical parameters of the nucleic acid backbone and bases through various chemical modifications, changing the physical and chemical properties to achieve both high solubility and nuclease resistance simultaneously
Data Source
AI summary
The present disclosure provides an anti-VEGF aptamer, an agent or composition comprising the anti-VEGF aptamer, as well as uses thereof.